Radiation handling system and set

ABSTRACT

A radioactive material such as an unstable isotopic gas is provided to a receiving chamber ( 1 ) directly from a source to form a purified or enriched bubble. The bubble is passed to a fluid handling set for preparation of the reagent or other delivery system. In an exemplary embodiment trace amounts of nitrogen-13 are concentrated in a receiving chamber and passed into a small bubble of carrier gas. The carrier gas is then delivered into a fluid handling set. The fluid handling set connects to a pressure syringe ( 50 ) and a passive syringe ( 60 ), and further includes a plurality of flushable valves ( 22-27 ) interconnected as a closed unit by tubing ( 21 ) to form a switchable or finite state flow network in which the pressure syringe may back flush the tubing, mix the isotope in a delivery liquid, and transfer the mixed liquid to an output for diagnostic imaging or other use.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of provisional application Ser. No.60/083,133, filed Apr. 27, 1998.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

Not Applicable.

BACKGROUND OF THE INVENTION

The present invention relates to the preparation and use of radioactiveisotopes for biological purposes such as labeling, marking, imaging anddiagnostics. Such applications generally utilize a single elementcontaining minor amounts of an unstable isotope, which must be generallyformed into a simple compound that is incorporated into a solution orreagent which undergoes a known or predictable interaction with thebiological system being studied. Thus, for example, radionuclides areoften added as labels to a substance that binds to a nucleic acid toindicate the presence of a particular substrate, termination orfunctional group. Similarly, materials which are taken up by particularbiological systems may be labeled for treatment or imaging purposes.Aerosols or radio-labeled fluids may also be used for blood flow or lungfunction diagnostic imaging studies.

In general, it is necessary that radioactive materials be handled insuch a way as to not expose the operator to radiation. Thus they arepreferably handled under robotic control or automated conditions. It isdesirable that the radioisotopes involved have a short half life, so asto automatically limit the exposure of the subject to radiation, and tofacilitate proper disposal. However, materials with a short half lifecannot be compounded in advance or stored for lengthy times. Suchradionuclides must therefore be manufactured at or near to the site ofintended use. In these cases the purification and preparation of theradionuclide in a suitable delivery system must also be accomplishedlocally. The brevity of the nuclide half life may further complicate itshandling and processing. These factors have sometimes prevented theacceptance or use of otherwise worthwhile radionuclide-based procedures.

It would therefore be desirable to provide a convenient system forpreparing radionuclides for biological use.

It would also be desirable to provide such a system for handling aradionuclide in an automated fashion without exposing the operator toradiation.

It would further be desirable to provide such a system useful forshort-lived materials or small batches to enable the routine use of suchmaterials in individual procedures.

SUMMARY OF THE INVENTION

These and other desirable features are achieved in a system inaccordance with the present invention by providing a radioactive markermaterial such as an unstable isotopic gas to a receiving chamberdirectly from a source to undergo initial cleansing or concentration,and passing the material into a fluid handling set for automatedpreparation of the reagent or actual delivery system. In an exemplaryembodiment, trace amounts of ¹³N, created by proton bombardment of atarget at a cyclotron, pass to a receiving chamber, are cleansed andpass into a small bubble of carrier gas. The carrier gas is thendelivered into a fluid handling set. The fluid handling set includes orconnects to a pressure syringe and a passive syringe, and furtherincludes a plurality, of flushable valves interconnected by tubing in aclosed unit to form a flow network in which the pressure syringe mayback-flush the tubing, mix the isotope in a delivery liquid, andtransfer the mixed liquid to an output for diagnostic imaging or otheruse. The fluid handling set, which is a closed and preferably sterileunit, may include the receiving chamber 1, and it mounts in a fixedconsole of operating motors and condition sensors to control the varioussteps of fluid handling and delivery, and to effect safety functionswhich enable the system to connect directly to a catheter or to avascular injection system for use on human beings.

In a preferred embodiment, the receiving chamber 1 is substantiallyrigid, but has a region of limited or unidirectional compliance. Thechamber receives a flow of trace isotope in a bulk gas, operating toremove the bulk gas while the radionuclide accumulates in a bubble atthe outlet port of the chamber. Compliance of the receiving chamber maybe effected by means of an elastic wall tensioned against a rigidsupport such that the wall flexes outwardly under pressure toaccommodate the inflow of carrier gas but may not bow inwardly. Thismaintains the chamber volume above a fixed minimum, and prevents liquidfrom leaving the chamber when suction is applied at the top. In anillustrative system, nitrogen-13 is generated by cyclotron bombardmentof a target with accelerated particles, and when the target has attaineda sufficient level of radioactivity, the sample is passed to thereceiving chamber and the CO₂ with trace ¹³NN is bubbled into a sodiumhydroxide solution. The one-way compliant wall allows a large flow to bereceived and maintained under pressure to accommodate the differentrates of carrier delivery and carrier removal effected at this stage.The CO₂ reacts with and is effectively taken up by the sodium hydroxidesolution, while the desired nuclide concentrates at a gas-filled plenumat the top of the receiving chamber, where it is accessed at the outletport using a closed sterile set to effect transfer, mixing and deliveryin a form useful for medical imaging. The fluid handling set includes aplurality of three way valves or medical infusion stopcocks that arepreconnected together via small bore tubing to form a flow path. Two ofthe stopcocks each have a third port, which are attached to syringebodies. One operates as an active bidirectional pump, while variousmotors and sensors in the console operate and control the position ofthe stopcock handles to achieve transfer, mixing and delivery of theradionuclide.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be more fully understood from the following detaileddescription taken in conjunction with the accompanying drawings, inwhich:

FIG. 1 is a flow chart illustrating major steps of the preparationprocess of the present system:

FIG. 1A illustrates the system showing representative components in usefor positron emission tomography;

FIG. 2 illustrates system architecture as applied to a nitrogen 13radionuclide;

FIG. 3 illustrates a preferred construction of a receiving chamber forthe system of FIG. 2;

FIGS. 4A through 4D illustrate details of valve operation and flow fortransfer of the radionuclide into a fluid handling set of the presentinvention;

FIG. 5 illustrates an operating console for the set of the invention;

FIGS. 5A-5C illustrate stopcock mounting and control blocks of theconsole for use with a closed sterile set; and

FIG. 6 illustrates another embodiment of the system and set.

DETAILED DESCRIPTION OF THE DRAWINGS

In accordance with a principal aspect of the present invention, there isprovided a system for automated and isolated handling of a hazardousmaterial, such as a radionuclide, for biological or medical use. Thesystem includes a sterile set defining the path of the nuclide from asource or process chamber to its end use which, in the illustratedembodiment, involves injection into a patient. Other potential end usesmay include specialized labeling, microanalytic or synthesisapplications. As shown in FIG. 1 for a representative system, theradionuclide, which in this case is nitrogen-13, passes from a source toa conditioning or purification chamber 1 which produces a small mass orbubble of the concentrated radionuclide for delivery to the preparationportion 10 of the system. The preparation portion 10 dissolves thenuclide in a saline solution for injection in a patient, and maydirectly inject the prepared solution into the patient.

By way of technical background for this embodiment, the use ofnitrogen-13 in gaseous form for medical imaging procedures was pioneeredat the Hammersmith Hospital, in London, several decades ago. Theradionuclide is produced by bombardment in a cyclotron using a number ofpossible target systems and sweep gases. Further details may be found inthe text Short-lived Radioactive Gases for Clinical Use of J. C. Clarkand P. D. Buckingham (Butterworth, London and Boston) pp 190-200. Thattext is hereby incorporated herein by reference. Nitrogen-13 is onlyvery slightly soluble in blood, and when injected in solution in theblood stream, quickly leaves the blood and accumulates at the blood-airexchange interface in the lung. Its decay creates positrons which mayprovide excellent three dimensional PET images of the lung, forevaluation of both perfusion and ventilation. However, the difficultiesof using this radionuclide have effectively prevented its adoption inhospital settings. Much of the discussion below is applicable to othergaseous radionuclides such as oxygen-15, or radionuclides incorporatedin a gaseous medium, or in a liquid with appropriate modifications.However, the preparation and use of nitrogen-13 presents a number oftechnical difficulties and will therefore be discussed more fully toillustrate aspects of a system and components of the present invention.

In accordance with a principal aspect of the present invention thesource radionuclide is provided in a relatively crude or bulk form, forexample in a sweep gas or target fluid from a cyclotron, or in otherprimitive or inter mediate form, and flows through the system todirectly enter the patient or be applied to some other sterile orpurified application such as marking, analysis or synthesis of a pureproduct. As shown in FIG. 1A it is generally contemplated that thesystem 20 will be a small cabinet, desktop or other stand-alone unitcontaining the sub-assemblies 1, 10 (FIG. 1), and which attaches to thesource and to tie patient either directly or via a small intermediateassembly. For example, the unit 20 may connect to the source through afiltration unit or the like, and to the patient via an infusion line,port or pressurized timed injector or the like. However, most preferablythe connection to the source and to the patient are as direct aspossible so that little dead space, wasted volume, delay time or regionsof radiation exposure are interposed between the source and the patient.

As further shown in FIG. 1A, the invention generally contemplates thatthe unit 20 will be controlled as to several parameters discussed belowby a connection to a keyboard/processor assembly 21. Also the specificnitrogen-13 embodiment is used in conjunction with an imaging ordetection assembly 25. The assembly 25 of FIG. 1A is a detector arraywhich encircles the patient and is configured for positron emissiontomography, to simultaneously detect the pair of annihilation photonsemitted in opposite directions by positron-electron annihilations as theradionuclide decays. The detector 25 provides its detection signals to aprocessor for construction of a three dimensional image of thedistribution of the positron-emitting radionuclide. Other suitabledetectors include single-sided detector arrays, or even photographicplate cameras which register and record the received annihilationphotons on a plate of film. However, a positron emission tomography(PET) instrument is the preferred detection instrument for theillustrated process.

FIG. 2 illustrates functional component of the units 1, 10 of FIG. 1. Asshown, the unit 1 for carrying out preliminary cleansing or refinementof the radionuclide in this case includes an absorbing chamber throughwhich the nitrogen-13 bubbles to remove the CO₂ sweep or residual targetgas as the material arrives from the cyclotron source. The absorbingchamber 1 is filled with sodium hydroxide solution and is shaped with aninverted funnel cap that channels unabsorbed gas upward to a plenum 1 aat the top of the chamber. Plenum 1 a connects on the one hand to anexhaust port 2 controlled by an exhaust valve 3 and, on the other hand,to an outlet port 4 controlled by transfer valve 5. The outlet portconnects to the main process line 21 of the sub-assembly 10, which asnoted above resides within the preparation console 20 (FIG. 1A) formingan inlet thereof and extending therethrough to the patient or end use.As described further below, chamber 1 may also be located within theconsole 20.

As further shown in FIG. 2, the functional flow control and handlingunits appearing in the preparation console 20 include in addition to theflow line 21 a plurality of sterile three-way valves or stopcocks 22, .. . 27 each of which has two of its three ports connected to the line21, and its third port connected to an inlet, outlet or syringe. Thedistal end of line 21 forms the output path from console 20. Each of thestopcocks 22-27 may be identical, and advantageously the stopcockstogether with tube 21 are connected together and initially provided as aclosed and sterile unit packaged in a manner similar, for example, to amedical infusion set. Each stopcock thus has one “free” port which isconnected to allow material to enter, leave, or be moved along line 21.These third ports are attached to a source of sterile saline fluid 40,an active injector syringe 50, a source of flush fluid, and a passiveholding syringe 60. In addition, a sample syringe 70 connects atstopcock 26, and an outlet line 80 to a dump, or waste vessel, extendsfrom stopcock 27. These elements may also be connected as part of theset, although, as will be understood from the discussion below,variations are possible. The function of the sample syringe may beimplemented instead by providing a small plenum with a pierceable septumconnected to the third port of stopcock 26, and the line 80 may simplyterminate with a spike port for attaching to a suitable collectionvessel or transfer mechanism.

As further illustrated in FIG. 2, the passive syringe is spring loadedso that it is normally biased to a non-extended, closed or minimalvolume configuration. Thus, when a pressurized flow appears along line21 and is directed into the syringe 60 by stopcock 25, its piston movesoutwardly to form an adaptive chamber that changes volume under pressurefor receiving the fluid in the line 21.

In accordance with a principal aspect of the present invention, thesterile set 21 includes a set of connected stopcocks and a syringe 50all configured to fit within the control console (described furtherbelow) and to be manipulated by servomotor elements therein to carry outthe radionuclide preparation and delivery to the patient. In arepresentative preparation and delivery protocol, the stopcocks are setto positions such that one or more stopcocks block the inlet, outlet orintermediate portion of the set, while one or more stopcocks are open tointerconnect various portions of the path for receiving, preparing ordelivering the radionuclide. In particular, the set 21 defines a finitestate flow path formed of sterile single use disposable elements thatfit within a console adapted to secure and control both sets ofelements. Advantageously, the console 20 may be configured as a cabinethaving separate compartments and which may, for example, be hinged toopen for inserting and changing the set. In the prototype, the receivingchamber 1 is housed in the back half with its outlet line 4 (FIG. 1A)connecting through the middle wall of the cabinet so that the fluid line21 (FIG. 2), runs through an array of stopcock or syringe receivingrecesses and control elements laid out along a path in the front half ofthe cabinet.

In this embodiment, the apparatus is conveniently divided into thoseparts that do not contact the sterile solution, and those parts whichdo. The parts which contact the saline directly are sterile, and areassembled from disposable medical components. These include all of thetubing downstream of the liquid detector, the stopcocks, and the threesyringes 50, 60, 70 which are disposable, and are to be replaced foreach patient. These components are mounted on the front panel of themain unit, so that they can be changed quickly. The remaining parts ofthe system do not contact the saline, and may advantageously be made ofreusable components. Thus the absorbing chamber 1, and the varioussolenoid valves and tubing that connect to it may be permanentlyinstalled. Preferably, the system is enclosed in a cabinet which isconnected to a high flow-rate vacuum to maintain a steady flow into thecabinet through its small openings, so that any leaks of radioactivitywithin the system are contained and the radioactive material is removed.

The cabinet is divided into three compartments. The rear compartment,accessible via a rear door, contains the absorbing chamber and a dumptank. This compartment is watertight so that a catastrophic failure ofthe absorbing chamber will not result in escape of sodium hydroxide. Acentral compartment houses all of the electronics of the apparatus, andis protected from contact with any liquid that may leak from a failingcomponent or connection. The front of the cabinet forms a door whichencloses the front panel, allowing easy access to components of thesystem that need to be changed frequently. Preferably the syringes mounton this panel.

FIG. 3 shows a preferred construction for the receiving chamber 1, whichmay be formed of a strong medical grade polymer. As shown, the receivingvessel 1 is configured with a rigid housing 101 which may for example beformed of a hard plastic and having an interior with a major lowerportion configured with a sloped roof leading to a chimney-like upperportion or outlet plenum 109 of defined volume. The vessel 101 isconfigured to fit on a magnetic base such as a stand having aninternally mounted rotating permanent magnet driver mechanism positionedbelow the chamber support surface, and a magnetic stirring rod 107 ispositioned in the bottom of the vessel 1. The main chamber communicatesthrough a passage 102 to a secondary chamber 101 a bounded by a flexibleelastic membrane or wall 104 positioned over the passage 102. Thisserves as a compliant chamber; the membrane 104 bends outwardly aspressure increases in the chamber 1 and fluid flows through the passageinto the secondary chamber. However, housing 101 is rigid and thepassage 102 is relatively small, or else may consist of a number ofsmall passages such that the wall below the flexible sheet 104 forms aperforated plate that supports the sheet and effectively prevents thesheet 104 from moving inwardly in response to negative pressure. Thisarrangement provides a stable volume within chamber 1, and accommodatesa large influx of fluid so that when radioactive material from thecyclotron enters the inlet, a large bolus of material may be received,increasing the pressure and allowing the material to more effectivelyreact in the absorbing chamber at the slower process rate of absorptiontherein. As discussed briefly above for the illustrated CO₂/nitrogen-13material, chamber 1 is filled with a sodium hydroxide solution and isgently stirred by a magnetic stirring rod, so the solution quicklyreacts with and effectively removes all the CO₂ while the unreactivenitrogen tracer rises into the outlet plenum 109 at the top of thechamber.

Preferably, for this process, the plenum 109 is initially loaded with asmall volume, e.g. a few cubic centimeters, of a carrier gas in whichthe nitrogen-13 is soluble. This carrier may, for example, be nitrousoxide or other suitable biocompatible gas. It is also advantageous thatthe carrier be highly soluble in blood or aqueous solutions, so that asdiscussed further below, problems of bubble formation or potentialdanger of bends are avoided. Thus, operation of the receiving chamber 1is such that the sweep gas or target predecessor material from thesource is removed, and the cleansed or concentrated radionuclide residesin the plenum 109 with a carrier gas for transfer through the transfervalve to the flow path 21. The architecture of vessel 1 thereforeretains the pocket of gas at the top of the chamber intact. In this way,no liquid infiltrates the tubing leading to the rest of the apparatus,where small droplets of liquid might cause false triggering of theliquid detector or blocking of the hydrophobic filter.

An important aspect of the design of the compliant compartment is thatit is only compliant to positive volumes. That is, volume can be addedto the chamber, but not withdrawn. Once the carbon dioxide is absorbed,and the bubble of nitrogen withdrawn, the membrane wall lies flatagainst the side wall of the chamber, and the chamber becomes rigid.Thus it is impossible to suck significant volumes of sodium hydroxideout of the absorbing chamber and into the rest of the system.

Skipping ahead to FIG. 5, there is shown a representative front panel ofthe console assembly 20 with the radionuclide entry port and elements ofthe flow path 21 laid out thereon. As shown, the flow line 21 firstpasses through a liquid detector which detects the arrival of liquid inthe flow line from the chamber 1 and provides a control signal used, asdescribed further below, for switching the states of the variousstopcocks and transporting the bubble of radionuclide through theprocessing stages of the preparation assembly 10.

As further shown in FIG. 5 a hydrophobic filter 29 b is placed in theflow line 21 as a barrier to entry of liquid from chamber 1 into thesystem 10. As shown, the fluid preparation line 21 or set, is positionedin the console 20 such that each of the stopcocks 22-27 fits within acorresponding receiving block 22 a through 27 a, and the injectionsyringe 50 and passive syringe 60 fit within a driver mounting 50 a anda syringe support 60 a, respectively. By way of example, the driverassembly for the injector syringe may be that of, or similar to, amanual or programmed contrast agent injector system capable of operationto drive a standard disposable syringe at high pressures through one ormore precisely timed and controlled displacements to inject preset dosesor volumes into the vascular system of a patient. The mounting 60 a forthe passive syringe may include a spring-loaded or counter-weightedplatform or pushing member against which the distal end of the plungerof the injection syringe rides, so that the biased member returns thepiston to its upper position (as shown) when the state of the stopcocksallows flow and the pressure in line 21 drops below the spring biasthreshold.

In the prototype embodiment, the injector drive consisted of a MedRadradiographic contrast injection instrument, and the remainder of thecabinet and control mechanism of unit 20 was built atop the injectormount so that the active syringe was conveniently located in immediateproximity to the other elements shown in FIG. 2. The stopcock mountingassemblies were prepared as shown in FIGS. 5A through 5C, byconstructing shaped plastic receiving blocks having recesses each shapedto accept a standard disposable stopcock assembly therein and to mounton a plate so that each stopcock engages a position reporting actuatormechanism, which turns the handle of the stopcock. The stopcock wasplaced into the housing with the handle facing forward and the housingwas designed to grip the three fluid connecting stubs of the stopcock,thus securely holding the stopcock body in a fixed position that allowedstopcock position to be controlled to within about one degree. A moldedcoupling was used to connect the stopcock handle to a standardservomotor, which in turn was controlled by a microcontroller boardconnected via a serial line to a computer used to control the apparatus.The computer was programmed to control operation of the stopcocks todefine different segments for receiving, transferring, mixing anddelivering the material. It was also programmed to control the injectionregimen of the syringe for delivery of prepared doses to the patient.

In the prototype embodiment, the servomotor assemblies were modified sothat the output of an internal potentiometer was passed to an A/Dconverter on the microcontroller board, and this output was used tocalibrate the stopcock positions and then continuously monitor theposition of each stopcock. Control software in the microprocessor with agraphical user interface allowed the user to set the position of thestopcock and displayed the position on the screen, signaling an alarm ifa motor fails to drive a stopcock element to the programmed position.For preparing the nitrogen-13 tracer, the program was written to effecta sequence of control steps as described below, and delivery steps werecontrolled by using the injector both to control the preparation of thesolution and the injection into the patient.

FIG. 4 illustrates a particular sequence for transfer of the tracerbubble from the absorbing chamber 1 into the mixing syringe, which isperformed by encapsulating the tracer bubble with a saline solution. Inbroad terms, the operating sequence proceeded as follows. Before gas isreceived from the cyclotron the system is readied for production.

The tubing from the absorbing chamber is flushed with a gas and theremainder of the apparatus is flushed and filled with de-gassed salinesolution. One suitable flush gas is nitrous oxide but many other gasesmay be used. The chief requirements are that the gas be biologicallysafe, soluble in water and be non-reactive with the reagents used(sodium hydroxide, in this case). The radioactive gas is then admittedto the absorbing chamber and is stirred with a magnetic stirrer untilall carbon dioxide is absorbed. Stirring is performed gently to avoidgeneration of droplets which might clog the hydrophobic filter 29 b(FIG. 5). The bubble of remaining gas at the top of the absorbingchamber is then transferred to the injector syringe which is otherwisefilled with an appropriate amount of de-gassed saline for thecontemplated infusion regiment or for the amount or availableradionuclide. The mixture in the injector is next dissolved byrepeatedly ejecting it into the passive syringe allowing its return andagain ejecting it, so that by the vigorous flow and atomizing action ofejection the tracer is quickly dissolved in the saline solution. Thisprocess of vigorous atomization mixing by repeated passage through aflow segment between syringes in a closed set thus effectively addressesthe difficult problem of preparing the radionuclide solution in a mannerthat is both safe and quick.

Next, with the stopcocks reset to define a different flow segment, asample of the injectate so prepared is expelled from the syringe intothe sampling syringe 80. Preferably a pH sensor is also present in theapparatus downstream of the injector syringe to detect any sodiumhydroxide contamination which may have occurred, and to actuate ashutdown in that event. The strength of the prepared solution isdetermined and this data is entered in suitable program for theinjection control or image processing. The stopcock configurations areagain changed, and the injector then gives a rapid bolus of tracersolution along its output line into the patient.

Returning now to FIG. 4, there is shown a representative sequence ofstates of the finite state flow segment operating sequence of thedevice, illustrating in this case the initial radionuclide transfer fromthe receiving chamber 1 into the preparation set 10. After the initialsystem preparation and cleansing in chamber 1 are completed, the stateof the apparatus is as depicted in FIG. 4A. The upstream tubing (on theleft) of stopcock 22 is filled with flush gas and the downstream tubing(to the right) is filled with degassed saline. The syringe 50 is thenoperated to draw along line 21 so that, as shown in FIG. 4B the bubbleof radioactive gas is drawn out of the pocket 109 (FIG. 3), and towardthe injector syringe 50. Sodium hydroxide solution is also drawn out ofthe absorbing chamber 1 at the trailing edge of the bubble ofcarrier/tracer gas. A liquid detector 29 a is installed in the assembly10 about the line 21 just upstream of the first stopcock 22 to provide asignal when the sodium hydroxide reaches this point. The transfer valve(FIG. 3) is then closed, and the controller moves the first stopcock(FIG. 4C) to connect the saline reservoir and fill in behind the bubblewith saline solution from the reservoir. The bubble of tracer is thus“encapsulated” by saline solution as shown in FIG. 4D. This allowscontrolled transfer through the apparatus by operation of the injectorsyringe. A slight amount of tracer gas still residing in the firststopcock and liquid detector is wasted. However, it will be understoodthat all tubing interconnecting the various components in the processingsection 10 is of small size (under one millimeter), of the typecustomarily used for transfer of small volumes of fluid, and thus thewasted tracer represents a very small proportion of the carrier/tracerbubble being processed.

After the bubble of gas is completely drawn into the injector syringe,the stopcocks are moved to define a new flow/transfer segment such thatthe injector outlet communicates only with the adjacent passive syringe.The mixture is then vigorously expelled into the passive syringe, thenagain drawn back into the active syringe and re-expelled. This processof repeated ejection promotes dissolution of the gas in several ways.Firstly, the surface area of the interface is increased exponentially byatomizing the fluid and in subsequent ejections breaking bubbles of gasinto many smaller bubbles. Secondly, the ejection occurs at elevatedpressure, thus enhancing the mechanisms of diffusion. Finally, thestrong current and highly turbulent flow during ejection mixes theliquid very well, reducing any concentration gradients that mightotherwise limit the process.

After the mixing process is complete, the stopcocks are againrepositioned and the syringe 50 is operated to expel to the dump avolume equal to the volume of gas originally drawn into the syringe.This assures that any undissolved gas is ejected from the system. Thelines to the patient are then flushed with the prepared tracer solution,and a small (1 ml) sample is taken. For the illustrated system, thesample is used primarily to assess the activity of the solution, but itcould be additionally analyzed to check the composition of theinjectate, or when applied to other radionuclide systems could determineother relevant conditions or parameters.

The pH of the solution is preferably measured by a sensor installed onthe line to the dump tank. Any sodium hydroxide contamination isdetected at this point, before injection to a patient.

In the foregoing system, it is important that the solution injected intothe patient not be super-saturated and not contain any gas bubbles. Ifthe solution were super-saturated, there would be a risk that bubblescould spontaneously appear in the solution before infusion or thatmicrobubbles of nitrogen would form in the bloodstream causing anartificially-induced form of decompression sickness (‘the bends’). Toassure that supersaturation does not occur, the volume of nitrogenwithdrawn from the absorbing chamber is limited to that volume which isknown to dissolve in the volume of saline being prepared, and followingdissolution, the mixture is allowed to equilibrate at atmosphericpressure. Thus, even if the solution is super-saturated, excess gas willdiffuse out of the solution. Further, when, following the mixingdescribed above, the volume at least as great as the volume of gasoriginally drawn in from the absorbing chamber is ejected from the topof the injector syringe to dump, both the excess undissolved gas and thegas that has come out of solution are expelled.

Preferably, an ultrasonic bubble detector is also installed on the lineto the patient, as well as a bubble-trap filter. Prior to injection, thelines are flushed, and a final, visual check for microbubbles isperformed.

FIG. 6 illustrates another embodiment of the system and set of thepresent invention. In this embodiment, the compliance chamber orflexible-walled side chamber may be actively pressed. This may be doneto assure complete return of the flexible wall, and thus further guardagainst expulsion of the sodium hydroxide solution. Furthermore, thestopcocks are located somewhat differently to provide a short directinfusion path to the patient, and to separate or shift other paths orpath segments. As in the first embodiment, the pressure syringe iscentrally located, and serves as a hub for drawing, expelling or movingfluid along the various segment defined by the states of the stopcockvalves. Advantageously, the pressure syringe mounts vertically, so thatit initially receives and segregates the gas, and subsequently expelsresidual bubbles to the dump.

For operation of the system, the saline may be drawn from a USP-standardinfusion bag, and all parts of the apparatus that contact the solutionare assembled using aseptic technique from sterile, disposable medicalcomponents. Microporous filters are installed on the line entering thesystem from the saline bag, and on the line out of the system to thepatient. Preferably a batch of tracer solution is prepared before thebatch intended for infusion, and a sample is assayed.

Preferably, the bolus infusion of tracer is given by the injector undercomputer control, with the computer programmed to accurately control theinfusate volume and rate, to effectively synchronize with a PET camera,and to automatically adjust dosage as the tracer decays. However,preferably the hardware is designed so that if necessary, the injectorcan be disconnected and operated manually. In the prototype embodimentusing an existing, manually-operated contrast media injector, theaddition of a microprocessor-based controller and other modificationsmade to the injector were such that all of its safety-features functionnormally, and when manually-operated, the injector was fundamentally thesame device as an unmodified, FDA-approved original. The seriesarchitecture of the treatment vessel and mixing assembly, together withthe unique bubble transfer mechanism and multiple redundant stops andoperation safety checks thus forms a system that is safely interposedbetween a cyclotron target and the patient's vasculature. Repetitiveejection between syringes produces a highly effective mixing/solutionmechanism using fungible disposables. Moreover, the provision of aclosed, disposable set for handling and compounding the radionuclide inan automated negative pressure safety cabinet allows the operator tomaintain a safe distance from radiation, and provides a convenientsystem for the remote handling and preparation of diverse medicines,reagents and tracer materials.

The invention has been described above in a particular application forreceiving, preparing and injecting a gaseous radionuclide for pulmonaryPET imaging. However, the unique remote handling, sterile mixing, andvolumetric control achieved by the set and the operating console areapplicable with slight changes to compounding and deliveringmedications, marking and synthesizing materials and otherradiation-handling tasks. Thus, it should be understood that theinvention is not to be limited by the particular embodiments shown anddiscussed above, but may take other forms and be embodied in diversesystems for preparing, reacting, formulating or delivering radionuclidesor biologically active materials. The invention and its principals ofoperation being thus disclosed, one skilled in the art will appreciatefurther features and advantages of the invention, and will be lead tofurther variations and modifications of the invention. Accordingly, allsuch variations and modifications are considered to be within the spiritand scope of applicant's invention as defined by claims appended heretoand equivalents thereof. All publications and references cited hereinare expressly incorporated herein by reference in their entirety.

What is claimed is:
 1. A system for preparation and delivery of abiologically active, hazardous or radioactive fluid, the systemcomprising a receiving system having a first port for receiving saidfluid and a second port positioned for delivering said fluid a fluidhandling set including a syringe and a plurality of flushable valvesinterconnected as a closed unit by tubing extending to an outlet thesyringe connecting via said fluid handling set to said second port andto said outlet for drawing the fluid into the tubing and transferringsaid fluid to the outlet as a prepared liquid and the fluid handling setbeing configured for operation of said valves to define a finite set offlow segments at different times in said set such that the syringeflushes, fills prepares and delivers the prepared fluid without exposingthe operator to radiation.
 2. A system for preparation and delivery of abiologically active, hazardous or radioactive material such as a gas,the system comprising a receiving chamber having a first port forreceiving said fluid and a second port positioned for accessing anactive gas present in said material an operating assembly for mounting afluid handling set including a pressure syringe, a passive syringe and aplurality of flushable valves interconnected as a closed unit by tubingsuch that tie tubing connects to said second port, and the operatingassembly being configured to secure and operate the pressure syringe andthe plurality of valves in sequence such that the pressure syringe drawsthe material into the pressure syringe and transfers the material withliquid to said passive syringe so as to form a prepared liquid, andfurther operating said valves to define a finite set of flow segments atdifferent times in said set for flushing, filling, preparing anddelivering the prepared liquid, to receive the material from a sourceand provide the prepared liquid to a patient.
 3. A system forpreparation and delivery of a biologically active, hazardous orradioactive material, the system comprising a receiving chamber having afirst port for receiving said material and a second port positioned foraccumulating a desired portion of the material a fluid handling setincluding a plurality of flushable valves interconnected as a closedunit by tubing and configured for automated remote operation of saidvalves to form a finite state flow path effective to receive andencapsulate said desired portion as a bubble, prepare said portion in adelivery liquid and transfer the delivery liquid to an output.
 4. Thesystem of claim 3, wherein said valves define flow segments at differenttimes in said set for flushing, filling, preparing and delivering thematerial such that the set receives the material as a gas from a sourceand safely delivers the delivery liquid to the bloodstream of a patient.5. The system of claim 4, wherein the fluid handling set includes apressure syringe operable for drawing the material into the set, mixingthe delivery liquid, and delivering the delivery liquid into thebloodstream of a patient.
 6. The system of claim 3, wherein the systemprepares a gaseous radionuclide for injection to perform positronemission tomographic images of the patient.
 7. The system of claim 3,wherein the fluid handling set is sterile assembly and further comprisesand active syringe connected to one of said valves, and a passivesyringe connected to another of said valves for receiving liquid suchthat the set is operable to prepare said portion in said delivery liquidby ejecting said portion and delivery liquid from the active syringeinto the passive syringe.
 8. A system for sterile preparation of a fluidradionuclide for use, such system comprising a sterile flow setincluding an inlet, an outlet, a plurality of stopcocks arranged in asequence along a flow line to define a plurality of fluid transportsegments, and first and second syringes connected to the flow line beingoperable to form a sterile liquid solution of said radionuclide while itremains in the flow set by repeated ejection from said first syringe tosaid second syringe and return to said first syringe.
 9. A systemaccording to claim 8, wherein the sterile flow set includes at leastfive stopcocks.
 10. A system according to claim 8, wherein at least oneof said syringes attaches directly to a port of one of the stopcocks.11. A fluid handling set for use in receiving a hazardous fluid materialand forming a delivery liquid, such set comprising a plurality of atleast five stopcocks and tubing Interconnecting said plurality ofstopcocks to form a closed transport path for handling the hazardousfluid material, each stopcock further having a port for admittingmaterial to or expelling material from said closed transport path.
 12. Adevice for receiving a hazardous fluid material and forming a deliveryliquid such as a reagent, medicine or imaging agent containing saidfluid material, such device comprising a plurality of stopcockreceptacles arranged along a path, a corresponding plurality ofservomotors positioned and configured for individually controlling astopcock each being positioned in one of the receptacles, a syringedriver, and a controller operative to control said servomotors to form aset of flow segments along a closed transport path for handling thehazardous fluid material, and to control said syringe driver to drive asyringe so that the syringe draws said fluid material into the transportpath and moves the fluid material along ones of said flow segments so asto prepare and deliver the delivery fluid.
 13. The device of claim 12,further comprising a flow set including a plurality of stopcocksinterconnected by tubing to form a sterile flow path, an active syringeconnected to said flow path, and a passive syringe connected to saidflow path.
 14. The device of claim 13, wherein the controller isoperative to control said servomotors to define a path between theactive syringe and the passive syringe, and to prepare the fluidmaterial by repeated ejection of the material from the active syringe tothe passive syringe.